Efficacy of a Novel Prophylactic Scheme of Fosfomycin Trometamol in Patients Undergoing Endoscopic Surgery for Benign Prostatic Hyperplasia: Findings from a Prospective Monocentric Single-Arm Study

Round 1

Reviewer 1 Report

I have read with interest the manuscript submitted by Berrino et al.

- in order to state that the treatment is effective, further analysis is required; or comparing the results with patients who did not receive any antibiotics, or to those who have received another regimen; What is the usual rate of infections/complications after these procedures, locally? What is the local protocol regarding the prophylaxis?

- the authors mentioned that is the first study investigating the efficacy of fosfomycin but then other very similar studies were presented;

The length of the manuscript is not sufficient, nor are the proportions (the material and methods section is longer than the results and the discussion section is limited). Further information should be inserted.

Avoid unnecessary self-citation.

Author Response

RESPONSE TO REVIEWERS

Manuscript ID: antibiotics-2990841 entitled “Efficacy of a novel prophylactic scheme of fosfomycin trometamol in patients undergoing endoscopic surgery for benign prostatic hyperplasia: findings from a prospective monocentric study” by Berrino et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewers’ constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision. Furthermore, as suggested by the reviewer #2, we performed a thorough review of the language to ensure clarity.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #1

I have read with interest the manuscript submitted by Berrino et al.

Q1. In order to state that the treatment is effective, further analysis is required; or comparing the results with patients who did not receive any antibiotics, or to those who have received another regimen; What is the usual rate of infections/complications after these procedures, locally? What is the local protocol regarding the prophylaxis?

A1. We thank the reviewer for this comment, and we agree with the fact that the absence of a comparator group represented the main limitation of our study. This might have prevented us drawing firm conclusions about the clinical efficacy of the proposed novel prophylactic fosfomycin trometamol regimen. We specifically discussed this issue more deeply in the Limitations section (refer to Line 300-310). Generally speaking, as stated in the Introduction, both TURP and HoLEP are classified as clean-contaminated interventions carrying an infectious risk of 4-10%, so that antibiotic prophylaxis is needed. In regard to the local protocol of antimicrobial prophylaxis in patients undergoing HoLEP and/or TURP, this is based on a single pre-operative dose of cefazolin. Unfortunately, local prevalence data of infectious complications after HoLEP and/or TURP procedures are unavailable, so that we could not compare current data with those of an historical. However, in order to overcome this issue, we compared our findings in terms of fever occurrence at 48-hours after intervention and documented UTI/urosepsis with those retrieved in previously published studies concerning prophylaxis with fosfomycin or with other antimicrobial agents (i.e., amoxicillin, cotrimoxazole) (refer to Discussion section, Line 303-310).

Q2. The authors mentioned that is the first study investigating the efficacy of fosfomycin but then other very similar studies were presented.

A2. We thank the reviewer for this comment, allowing us to clarify better this aspect. Indeed, several studies previously just evaluated previously the clinical efficacy of fosfomycin as antibiotic prophylaxis in patients undergoing urological procedures. all of these adopted a prophylactic/pre-emptive strategy based on one dose 3h before and a second one 24h after the intervention. As stated in the discussion of our Ms., this prophylactic regimen may be burdened by suboptimal attainment of prostatic fosfomycin concentrations in those patients who undergo surgical procedure early after the first fosfomycin dose due to a delayed distribution in the prostatic tissue, as previously reported (refer to doi:10.1093/jac/dkv067). Our prophylactic scheme is novel because it is the first based on two pre-operative doses 12h apart. This approach may minimize the likelihood of having suboptimal prostatic concentrations under these circumstances (refer to Discussion section, Line 269-294). We addressed this issue in the Introduction section (refer to Line 78-89).

Q3. The length of the manuscript is not sufficient, nor are the proportions (the material and methods section is longer than the results and the discussion section is limited). Further information should be inserted.

A3. We thank the reviewer for this suggestion. The whole length of the text was extended, as per required. In regard to the proportion between the different sections of the manuscript, we discussed more deeply the findings of our study in the Discussion and Limitations sections. Additionally, the Results section was extended furtherly by adding some procedural details.

Q4. Avoid unnecessary self-citation.

A4. Thank you for this suggestion. We removed unnecessary self-citations, which are now 3 out of the overall 36 citations (< 10%).

Reviewer 2 Report

In this study, Berrino et al. have studied the efficacy of a new approach for the use and administration of fosfomycin trometamol as a prophylactic, for those undergoing HoLEP or TURP for BPI. In total, 96 patients were considered for this study. Two doses of the drug were administered to the patients 12 h apart, at 8pm on the day prior to surgery and at 8am on the day of surgery. Data was collected and statistical analyses were performed to recognize the superiority of this approach over the other methods.

                The manuscript was well written – enough introduction was provided to discuss the problem, the methods were clear, and the discussion was fair and gives an overview about previous studies. However, the design of the study may be improved – the authors have already acknowledged that the control group was missing in the study. It may be difficult to conclude without randomization and control groups. Although the authors have concluded that this scheme may be beneficial to the patients, it is also important to be very cautious before publishing as these studies can affect the decisions of a doctor at a clinical setting.  It is for this reason that I think the study is incomplete and recommend major changes in the manuscript.

Minor comments:

1)      PSA (abbreviation), though first introduced at L111 is defined later in the manuscript at L139.

2)      The text in Table 1 may be left aligned – this will help readers follow the text easily.

Author Response

RESPONSE TO REVIEWERS

Manuscript ID: antibiotics-2990841 entitled “Efficacy of a novel prophylactic scheme of fosfomycin trometamol in patients undergoing endoscopic surgery for benign prostatic hyperplasia: findings from a prospective monocentric study” by Berrino et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewers’ constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision. Furthermore, as suggested by the reviewer #2, we performed a thorough review of the language to ensure clarity.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #2

Q1. In this study, Berrino et al. have studied the efficacy of a new approach for the use and administration of fosfomycin trometamol as a prophylactic, for those undergoing HoLEP or TURP for BPI. In total, 96 patients were considered for this study. Two doses of the drug were administered to the patients 12 h apart, at 8pm on the day prior to surgery and at 8am on the day of surgery. Data was collected and statistical analyses were performed to recognize the superiority of this approach over the other methods.

The manuscript was well written – enough introduction was provided to discuss the problem, the methods were clear, and the discussion was fair and gives an overview about previous studies. However, the design of the study may be improved – the authors have already acknowledged that the control group was missing in the study. It may be difficult to conclude without randomization and control groups. Although the authors have concluded that this scheme may be beneficial to the patients, it is also important to be very cautious before publishing as these studies can affect the decisions of a doctor at a clinical setting.  It is for this reason that I think the study is incomplete and recommend major changes in the manuscript.

A1. We thank the reviewer for appreciating our manuscript and for this relevant comment. We thank the reviewer for this comment, and we agree with the fact that the absence of a comparator group represented the main limitation of our study. This might have prevented us drawing firm conclusions about the clinical efficacy of the proposed novel prophylactic fosfomycin trometamol regimen. We specifically discussed this issue more deeply in the Limitations section (refer to Line 300-310). However, in order to overcome this issue, we compared our findings in terms of fever occurrence at 48-hours after intervention and documented UTI/urosepsis with those retrieved in previously published studies concerning prophylaxis with fosfomycin or with other antimicrobial agents (i.e., amoxicillin, cotrimoxazole) (refer to Discussion section, Line 303-310).

Minor comments:

Q2. PSA (abbreviation), though first introduced at L111 is defined later in the manuscript at L139.

A2. Thank you for this suggestion. We defined PSA at first introduction (refer to Line 129-130).

Q3. The text in Table 1 may be left aligned – this will help readers follow the text easily.

A3. Thank you for this suggestion. We left aligned the text in Table 1 for improving readability.

Reviewer 3 Report

This study provides a novel prophylaxis treatment strategy for patients undergoing HoLEP or TURP for BPH. It is suggested to consider the following corrections and suggestions to further improve the quality of the manuscript.

The lack of a control  or comparison group in this study is one of the significant drawbacks to drawing conclusions about the effectiveness of Fosfomycin. Consequently, there is a lack of statistically significant values to support the outcomes of this study. However, the authors have addressed these points very briefly as drawbacks of the study in the discussion section more through discussion is required.

The phrasing of the text in the lines 26 -31 “Prevalences 26 of fever occurrence in the first 48-hours after surgical procedure, of urological complications occurring after the surgical procedure, of proven urinary tract infections (UTIs) and/or bloodstream infections (BSIs) at 14-days, of emergency department admission for UTI-related sepsis at 14-days were assessed. Univariate analysis comparing patients having or not at 14-day proven UTI, BSI, or emergency department admission was carried out.” could be improved for clarity and readability.

In the introduction section, the authors should address why the aim of this study is novel compared to other studies.

Correct the spelling of ‘minim’ in line 52.

It is suggested to provide a brief pharmacological overview of fosfomycin trometamol in the introduction section.

Provide the full form of “IRCSS” in line 80.

The grammar of the text in lines 86-89 could be improved for clarity.

It should be ‘as follows’ instead of as follow in line 99.

Language-related concerns, such as unclear phrases, spelling and grammatical errors, are present throughout the manuscript. It is suggested that the authors conduct a thorough review of the language to ensure clarity.

Author Response

RESPONSE TO REVIEWERS

Manuscript ID: antibiotics-2990841 entitled “Efficacy of a novel prophylactic scheme of fosfomycin trometamol in patients undergoing endoscopic surgery for benign prostatic hyperplasia: findings from a prospective monocentric study” by Berrino et al.

Dear Editor,

We would like to thank you for the opportunity to resubmit a revised version of this manuscript. We appreciated the reviewers’ constructive comments. All have been carefully considered and incorporated, where and whenever possible, in the revision. Furthermore, as suggested by the reviewer #2, we performed a thorough review of the language to ensure clarity.

Our point-by-point responses are provided below.

Q= QUERY; A= ANSWER

Reviewer #3

This study provides a novel prophylaxis treatment strategy for patients undergoing HoLEP or TURP for BPH. It is suggested to consider the following corrections and suggestions to further improve the quality of the manuscript.

We thank the reviewer for appreciating our manuscript.

Q1. The lack of a control  or comparison group in this study is one of the significant drawbacks to drawing conclusions about the effectiveness of Fosfomycin. Consequently, there is a lack of statistically significant values to support the outcomes of this study. However, the authors have addressed these points very briefly as drawbacks of the study in the discussion section more through discussion is required.

A1. We thank the reviewer for this comment, and we agree that lacking of a control/comparison group may represent the main limitation of our study. As suggested, we discussed more deeply this issue in the Limitations section (refer to Line 300-310).

Q2. The phrasing of the text in the lines 26 -31 “Prevalences 26 of fever occurrence in the first 48-hours after surgical procedure, of urological complications occurring after the surgical procedure, of proven urinary tract infections (UTIs) and/or bloodstream infections (BSIs) at 14-days, of emergency department admission for UTI-related sepsis at 14-days were assessed. Univariate analysis comparing patients having or not at 14-day proven UTI, BSI, or emergency department admission was carried out.” could be improved for clarity and readability.

A2. We thank the reviewer for this comment. We modified the sentence for improving clarity and readability as suggested (refer to Abstract section, Line 27-30).

Q3. In the introduction section, the authors should address why the aim of this study is novel compared to other studies.

A3. We thank the reviewer for this comment, allowing us to better clarify the novelty of our study. Indeed, several studies evaluated just previously the clinical efficacy of fosfomycin as antibiotic prophylaxis in patients undergoing urological procedures. All of these adopted a prophylactic/pre-emptive strategy which was based on one dose 3h before the intervention and a second one 24h after the intervention. As stated in our Ms., this prophylactic/preemptive regimen may be burdened by suboptimal attainment of prostatic fosfomycin concentrations in those patients undergoing the surgical procedure early after the first fosfomycin dose due to a delayed distribution in the prostatic tissue, as previously reported (refer to doi:10.1093/jac/dkv067). Our prophylactic scheme is novel because is the first one based on  two pre-operative doses 12h apart. This approach may minimize the likelihood of having suboptimal prostatic concentrations under these circumstances. Additionally, our novel prophylactic scheme may have the theoretical advantage of abating any eventual bacterial load associated with an asymptomatic bacteriuria that should occur immediately before the intervention. (refer to Discussion section, Line 269-294). We addressed this issue in the Introduction section (refer to Line 78-89).

Q4. Correct the spelling of ‘minim’ in line 52.

A4. Thank you for this suggestion. We corrected it accordingly (refer to Line 53).

Q5. It is suggested to provide a brief pharmacological overview of fosfomycin trometamol in the introduction section.

A5. We thank the reviewer for this useful suggestion. We provided a brief pharmacological overview of fosfomycin trometamol in the Introduction section (refer to Line 67-73).

Q6. Provide the full form of “IRCSS” in line 80.

A6. Thank you for this suggestion. We provided the full form of “IRCCS” (refer to Line 96-97).

Q7. The grammar of the text in lines 86-89 could be improved for clarity.

A7. Thank you for this suggestion. We modified the sentence accordingly for improving clarity and readability (refer to Line 102-106).

Q8. It should be ‘as follows’ instead of as follow in line 99.

A8. Thank you for this suggestion. We modified it accordingly (refer to Line 117).

Round 2

Reviewer 1 Report

I appreciate the author's efforts in addressing my comments. The quality of the manuscript has significantly improved and can be published in its current form, in my opinion.

Reviewer 2 Report

I appreciate the authors for making the proposed minor changes. However, I am unable to accept the manuscript in present form as control groups are extremely important to study the effect of the new therapeutic strategy. While I acknowledge the motivations for publishing research findings expeditiously, I respectfully encourage the authors to dedicate additional time to thoroughly investigating the true impact of the novel treatment regimen before releasing their results.

Reviewer 3 Report

The authors have sufficiently addressed the suggestions raised, and the changes made by the authors are reviewed.